The carcinoembryonic cell adhesion molecule (CEACAM) family of membrane proteins has been known for many years as intestinal tumor markers with a role in innate host defense in mucosa of several tissues, however there have been no previous detailed studies of CEACAMs in the lung. We initially identified CEACAM6 as an induced gene in human fetal lung epithelial cells undergoing hormone-stimulated differentiation into type 11 cells. Preliminary studies indicate that CEACAM6 in lung is developmentally regulated in vivo and is induced in cultured cells by thyroid transcription factor-1 (TTF-1), a key transcription factor in type 11 cells. In addition, CEACAM6 is found in lung fluid of infants and adults, associated in part with secreted surfactant, appears to be up-regulated in lung injury and infection, and has both anti-apoptotic and surfactant protective functions in vitro. Based on these and other observations, our primary hypothesis is that CEACAM6 is a regulated protein that is involved in alveolar host defense, Type II cell survival and surfactant function. Three aims are proposed to investigate expression, function and signaling pathways of CEACAM6. The basic studies of Aim 1 in human cells, utilizing a well-characterized primary culture system, explore CEACAM6 interaction with surfactant and effects on apoptosis and innate immune properties of type II cells using adenovirus transduction and siRNA approaches for gain and loss of function. DNA microarray analysis will identify genes regulated by CEACAM6 cross-linking and ligand binding. Aim 2 will investigate CEACAM6 functions in vivo using a novel transgenic mouse (CEABAC) that expresses the human protein. Experiments of Aim 3 will utilize a large repository of clinical samples and clinical data to determine the developmental pattern, cellular distribution and regulatory mechanisms of CEACAM6 expression in human lung as well as associations of postnatal levels in lung tissue and fluid with lung diseases of premature infants.